The present invention relates to improvements in and/or relating to the synchronising of animal oestrus and intra vaginal devices useful therein together with related means and methods.
It is useful for farmers to synchronise the oestrus of animals whether they be cattle beasts (whether for dairy or beef purposes) sheep, goats, horses, or the like where artificial insemination is practised. By way of example, in relation to cattle beasts, in a normal 365 day year 282 days on average is taken up of the year with the gestation period itself. With approximately 30 days to recover after delivery of its progeny each cow therefore has an average of only two and a half cycles if there is to be a timely management of the herd. Thus it is important over that remaining period of less than 53 days to ensure each cow in a herd becomes pregnant.
The traditional method of mating dairy cows with bulls is now largely superseded by the use of artificial insemination procedures which offer the prospect of rapid herd improvements although bulls are still presented to the herd frequently to catch those animals that have not conceived by the artificial insemination procedure.
There is therefore a great advantage attached to bringing such herd animals into oestrus simultaneously so as to make it easier to ensure effective usage of the artificial insemination procedure and subsequently to enable still within the xe2x80x9cwindowxe2x80x9d a further prospect of artificial insemination of those animals synchronistically brought to oestrus that have not already conceived.
Various means of achieving such a management of the synchronisation of the coming into oestrus of cows (whether heifers or lactating cows) and even sheep and goats has been disclosed in the art which includes the xe2x80x9cEAZI-BREED CIDR Controlled Breeding and Reproductive Managementxe2x80x9d booklet made available to interested parties by InterAg a division of the applicant company in respect of its intra vaginal Eazi-Breed(trademark) CIDRR product line.
The disclosures in the aforementioned publication, the fill contents of which are here included by way of reference, comprehensively describe treatment protocols applicable at least to New Zealand herds of cattle beasts for synchronising oestrus and treatment of anoestrus.
These treatment protocols often utilise Eazi-Breed(trademark) CIDRR devices in combination with drugs such as prostaglandin and/or oestradiol benzoate, and extend in general for periods of 7, 10 or 12 days.
If both control of the oestrus cycle and high fertility are to be optimised in cattle, studies have shown that an intra vaginal device must deliver sufficient progesterone (when used with combination drugs i.e. oestradiol or GnRH) to produce a minimum plasma progesterone concentration of 2 ng/mL over the terminal period of treatment (1,2).
1. Kesner, J. S., Padmanabhan, V. and Convey, E. M. Biol. Reprod. 26 (1982) 571-578.
2. Kinder, J. E., Kojima, F. N., Bergfeld, E. G. M., Wehrman, M. E. and Fike, K. E. J.Anim. Sci 74 (1996) 1424-1440.
A cost factor arises in the adoption of such protocols as a farmer is faced with the costs of the intra vaginal progesterone containing device as well as the use of the combination drugs. This ignores also the economic cost of the artificial breeding materials themselves.
The intra vaginal progesterone containing devices hitherto used in New Zealand and to a large extent elsewhere are typified by the CIDRR product of the applicant company depicted hereinafter in FIG. 1 being a variable geometry device for vaginal insertion and retention which comprises a structural frame of a metal or appropnate plastics material encased in a progesterone impregnated plastics material from which the material can leach in the vaginal environment and from which it can be timely withdrawn by appropriate means (e.g: a string, tail or a tool) to allow the animal to progress into oestus shortly after the removal. Hereinafter the aforementioned device will be referred to by its registered trademark CIDRR.
Another product available in the market place of this kind is another variable geometry device and such a device is depicted hereinafter in FIG. 2. Such a device is a helical coil capable of being helically tightened and which is retainable in its helical form in the animals vagina. The device includes a withdrawal cord and carries a gelatine capsule which includes oestradiol benzoate so that there can be co-administration of the progesterone to be released over a protracted period and the oestradiol benzoate which is to be released at a different rate. Such a device includes a progesterone impregnated plastics matrix about a helical spine. Such a device is available from Sanofi Animal Health Limited, PO Box 209, Rhodes Way, Watford, Herts, WD24QE, England under its registered trademark PRIDR.
The aforementioned CIDRR and PRIDR devices are manufactured in large volumes with the most expensive material being the progesterone active ingredient and thus small reductions in the progesterone inclusion in such devices will provide an economic advantage to a producer and to a farmer. Also any such reduction provides a reduced risk to the environment owing to a likely reduced residual amount of the progesterone in the matrix after the device has been withdrawn from an animal. This reduced residual amount not only provides safety but also dis-encourages the unrecommended reuse of a device in another animal where the unknown condition of such a device will give unpredictable results.
The CIDRR prior art device of the applicant company has been marketed with a silicone plastics matrix about its spine which contains about 1.9 grams of progesterone (USP) which drops to 1.33 grams still retained in the silicone matrix if the device is withdrawn after seven days. The same device drops to 1.05 grams of progesterone if it is not withdrawn until after 12 days.
The PRIDR coil intra vaginal device contains at the outset 1.55 grams of progesterone which reduces down to 1.18 grams after 7 days and down to 0.94 grams after 10 days. The leach rate from the PRIDR product may be affected in part by the inclusion of inorganic materials in the silicone plastics material such as calcium carbonate. The CIDRR silicone matrix is largely free of any such inclusions.
Hoechst U.S. Pat. No. 5,398,698 discloses the use of milled sheets of silicone rubber in intra-vaginal devices which carry progesterone. The milled sheets (2 to 10 mm thick) are vulcanised for from 4 to 8 minutes at from 70xc2x0 C. to 120xc2x0 C.
The accepted test for the delivery of progesterone or its metabolites to the appropriate site of action in order to postpone oestrus is by reference to the progesterone level in the blood plasma of the animal. The design of such devices has to date usually been on the basis of an acceptance of the Higuchi equation based on a square root of time model (see hereinafter) which suggests that progesterone inclusions in such a plastics matrix would achieve plasma levels which decline with time.
Our investigations have found surprisingly that it is inappropriate in the design of such intra vaginal devices to rely upon the Higuchi equation or the square root of time model. In our device release is constant with time up to 7 days resulting in constant steady state plasma levels over that time period.
We have determined that by modifying the levels of progesterone initially in a silicone matrix, by controlling the thickness of the silicone matrix over the spine and by giving attention to the surface area of the device savings to a manufacturer arising from reduced quantities of progesterone being needed while at the same time achieving the same blood levels can be achieved. Savings are also achieved over the prior art devices in terms of the amount of silicone used, since silicone is the second-most costly material used in the devices, with corresponding benefits being able to be passed on to the user.
The present invention relates to intra vaginal devices, methods of producing intra vaginal devices, and the use of such intra vaginal devices for managing oestrus and for the treatment of anoestrus in cattle, sheep, deer and goats.
In one aspect the invention is an intra vaginal device of a variable geometry kind capable of being applied into the vaginal cavity of an animal selected from the group consisting of cattle, sheep, deer and goats, retainable therein over a period of time within the range of from 7 to 12 days and then to be withdrawable therefrom to allow the onset of oestrus, said device being characterised in that:
a matrix of a cured silicone rubber material that includes greater than 5% by weight progesterone to the weight of the matrix defines an exterior surface (which may be all or part only of the device) of at least 75 cm2 contactable once inserted in the vagina of such an animal by the vaginal membrane and/or vaginal fluid(s) of the animal,
the matrix of progesterone containing silicone rubber material has been formed by injection of the uncured progesterone containing matrix as a liquid into a mould for a sufficient time to achieve at a mould temperature or temperatures within the range of from 100xc2x0 C. to 210xc2x0 C. and a shape retaining at least partial cure thereof,
the total progesterone load (irrespective of whether alpha or beta progesterone or mixtures thereof) being from 1 to 1.5 grams within said matrix,
said surface area is available to at least substantially all of the matrix for progesterone release over a thickness of no greater than about 1 millimeter, and
said device upon vaginal insertion into such an animal is able to achieve and then maintain in the animal for a least seven days a minimum progesterone blood plasma level of 2 nanograms per milliliter of plasma of the animal and which after seven days of insertion will have a residual load in the silicone rubber matrix of less than 65% by weight of its progesterone load at insertion.
Preferably said exterior surface is from 100 to 150 cm2, more preferably 120 to 125 cm2.
Preferably said matrix has about 10% by weight progesterone by weight of progesterone to the weight of matrix.
Preferably said matrix at least in part encases a deformable frame.
Preferably said frame is resilient.
Preferably said frame is substantially in the form of a xe2x80x9cTxe2x80x9d with the arms of the xe2x80x9cTxe2x80x9d being deformable to allow introduction into the vagina of an animal, the xe2x80x9cTxe2x80x9d form being defined by a resilient spine about which (at least in part) there is moulded said matrix.
Preferably said frame is of nylon.
Preferably after seven days from insertion the matrix will have a residual load of less than 60% by weight of its progesterone load at insertion.
In a further aspect the invention is an intra vaginal device of a variable geometry kind capable of being applied into the vaginal cavity of an animal selected from the group consisting of cattle, sheep, deer and goats, retainable therein over a period of time within the range of from 7 to 12 days and then to be withdrawable therefrom to allow the onset of oestrus, said device being characterised in that
on a frame or spine (hereafter xe2x80x9cframexe2x80x9d) of variable geometry there is a matrix of a cured silicone rubber material that includes greater than 5% and less than 20% by weight progesterone to the weight of the matrix defines and exterior surface (which may be all or part only of the device) of at least 100 cm2 contactable once inserted in the vagina of such an animal by the vaginal membrane and/or vaginal fluid(s) of the animal,
the matrix of progesterone containing silicone rubber material has been formed by injection of the uncured progesterone containing matrix as a liquid into a mould for a sufficient time to achieve at a mould temperature of temperatures within the range of from 190xc2x0 C. to 195xc2x0 C. and a shape retaining at least partial cure thereof,
the total progesterone load (irrespective of whether alpha or beta progesterone or mixtures thereof) being from 1 to 1.5 grams (preferably about 1.35 grams) within said matrix,
said surface area is available to at least substantially all of the matrix for progesterone release over a thickness of no greater than about 1 millimeter, and
said device upon vaginal insertion into such an animal is able to achieve and then maintain in the animal for at least seven days a minimum progesterone blood plasma level of 2 nanograms per milliliter of plasma of the animal and which after seven days from insertion will have a residual load in the silicone rubber matrix of less than 65% by weight of its progesterone load at insertion.
Preferably said device is substantially as herein defined with reference to any one or more of the accompanying drawings.
In still a further aspect the invention a method of postponing oestrus or treatment of anoestrus in an animal which includes the steps of
administering into said animal by means of an intra vaginal device sufficient progesterone from a progesterone impregnated silicone rubber matrix where the progesterone content in the matrix is 5% or greater by weight via a surface area greater than 75 cm2 so as to achieve on the last few days of insertion a progesterone blood plasma level of greater than 2 nanograms per milliliter, and
removing the device after an insertion period of from 7 to 12 days.
Preferably said device is as previously defined.
Preferably said method includes the administration of oestradiol at or near the time of insertion of said device.
Preferably said method includes the administration of a prostaglandin at about day 6 of about a 7 to 10 day device insertion period.
In still a further aspect the invention is, in a method of attempting to synchronise the onset of oestrus of a herd of cattle beasts, the procedure of
administering intra vaginally to each animal of the herd progesterone from an intra vaginal device of the present invention and
after an appropriate period of time removing such devices to allow the onset of oestrus (the procedure optionally including the steps of administration of oestradiol benzoate and/or prostaglandin etc. as known in the art or otherwise), said method being further characterised in that levels of progesterone in the blood plasma of each animal is greater than 2 nanograms per milliliter until such time as the devices are withdrawn.
In still a further aspect the invention consists in a method of synchronising the onset of oestrus in a herd of cattle beasts which comprises
administering by means of an intra vaginal device to each animal from a progesterone impregnated matrix of the device an effective amount of progesterone for the period the device is retained intra vaginally, the device having being administered with a progesterone quantity of about 1.35 grams and being removed with a progesterone quantity of the order of about 0.85 grams.
As used here in xe2x80x9csurface areaxe2x80x9d of the progesterone impregnated matrix is that area directly contactable by vaginal fluid(s) and/or membrane.
As used herein xe2x80x9csurface areaxe2x80x9d is independent of any surface area of the spine (if any) which may or may not be of a plastics material. However, thicknesses of the progesterone impregnated medium or matrix are to the surface of the spine.
While reference has been made to cattle beasts the device and method is believed to be equally applicable to other mammals, e.g. sheep, goat, horse, etc.